DESCRIPTION (Applicant's abstract): This small project grant proposal reapplication requests funding for a category 1 purpose (newer, less experienced investigators). We also believe that the study proposed is an important step in directing future biological research in the field of panic disorder a potentially disabling condition affecting 1-2% of the population. We have recently performed repeat clonidine challenges in panic disorder (PD) patients and controls with .15 mg of oral clonidine 12 weeks apart. Patients were treated with fluoxetine between challenges, whereas controls received no medications during this interval. We challenged 17 patients (13 repeats) and 16 controls (13 repeats). Of the 13 patients who were retested, 11 were judged as being at least much improved. Analysis of the data indicate that panic disorder patients did not show an increase in human growth hormone (HGH) response to either clonidine challenge despite intervening effective fluoxetine treatment. We have also demonstrated significantly reduced HGH response in PD patients relative to controls before and during fluoxetine treatment. The data suggest that blunted HGH responses to clonidine may have trait-like characteristics in panic disorder, as has been reported for affective illness (for review, see Siever et al, 1992). An alternative explanation is that fluoxetine independently blunted GH responses. Preclinical evidence suggests that serotonin agonists may under certain circumstances decrease growth hormone secretion. In order to potentially establish trait characteristics of the HGH response to clonidine in panic disorder, we are requesting to study PD and healthy control subjects who have achieved clinical improvement through cognitive/behavioral therapy (CBT) i.e. clinically improved unmedicated patients. We propose performing four serial clonidine challenges to address the question whether the blunted HGH response to clonidine remain reduced relative to controls when PD patients respond to CBT. We will assess biological response to clonidine at the three and six month mark to rule out the possibility that long-term improvement is required for biological normalization. In addition, we will challenge PD patients twice before treatment separated by one week in order to assess the stability of response in PD patients who remain acutely symptomatic. Establishing biological markers with trait-like characteristics is a critical priority in anxiety disorder research. The HGH response to clonidine is among the most replicated biological challenge paradigm in PD research. Such a biological marker, if validated, may permit early identification of subjects at-risk for the disorder, may be used in genetic linkage studies, may predict treatment response or relapse and may lead to an understanding of the etiopathogenesis of panic disorder through the study of the interaction of pre-existing vulnerability and clinical condition.